Treatments and formulations comprising Torsemide

ABSTRACT

Disclosed herein are treatments for diseases such as hypertension, diabetes, and congestive heart failure using controlled-release (CR, e.g., extended-release (ER) or prolonged-release (PR)) oral dosage formulations comprising an effective amount of Torsemide.

CROSS-REFERENCE TO RELATED APPLICATION(S)

The present application is a continuation in part of application Ser.No. 15/027,355 filed on Apr. 5, 2016, entitled “Controlled-ReleaseFormulations Comprising Torsemide” the entire disclosure of which isincorporated by reference herein.

FIELD OF THE INVENTION

The invention is directed to controlled-release (CR, e.g.,extended-release (ER) or prolonged-release (PR)) oral dosage formulationcomprising an effective amount of Torsemide or a pharmaceuticallyacceptable salt thereof and at least one controlled-release excipient.

BACKGROUND OF THE INVENTION

Congestive heart failure (CHF) affects 1.7% of the US population, 4.6million people have chronic heart failure, there are 550,000 new casesper annum and approximately 60% are over 70 years of age. Theetiological causative factors are coronary heart disease, hypertension,cardiac valvular disease, arrhythmias, cardiomyopathy and diabetes. Itis associated with high mortality. In the US the median survivalfollowing onset of CHF is 1.7 years in men and 3.2 years in women. Datagenerated from Scotland shows a 3-year mortality rate after firsthospitalization for CHF patients' age 65 years and older isapproximately 66%.

Diuretics play an essential role in modern cardiovascular therapy, andare currently recommended for the treatment of CHF. Diuretics sufferfrom many defects or complications including electrolyte and metabolicdisturbances and reduction in glomerular filtration rate (GFR). The GFRis already reduced in most patients with edematous conditions anddeclines further over time eventually mandating the use of loopdiuretics since these agents have the most potent acute pharmacologicalaction of natriuresis and diuresis. However, any further fall in GFRwill compromise the fluid and salt depleting actions of the diuretic andmay lead to a “cardiorenal syndrome.” Prior studies with furosemide innormal subjects consuming a high salt intake showed that furosemideincreased the GFR immediately after the dose, but reduced it thereafterby circa 23% during the remainder of the day.

Despite their unrivaled acute effectiveness, loop diuretics have beendisappointing therapeutic agents. They cause little or no reduction inblood pressure (BP) in hypertensives, resulting in a preference for lessacutely naturietic and diuretic drugs such as thiazides ormineralocorticosteroid antagonists (MRAs). Furosemide's short half-lifeand extreme variation in bioavailability may account for itsunpredictable effects in treating patients with CHF and bumetanide iseven more short acting.

A class defect of loop diuretics is their short duration of action of2-4 hours even after oral dosing. Two problems may ensue. First, theplasma concentration of the loop diuretic resides within the “mostefficient” 25% to 75% of maximum level for less than one hour. Second,their abrupt action leaves about 20 hours for the kidney to regain thesalt and water lost before the next daily dose. This accounted for thefailure of furosemides or bumetanide to cause net Na⁺ loss over 1-3 daysof once daily administration to normal subjects unless dietary salt wasrestricted.

Torsemide has been developed as a newer type of loop diuretic with alonger half-life, longer duration of action, and higher bioavailabilitycompared to the most commonly used loop diuretic, furosemide.

Torsemide is routinely used for the treatment of both acute and chronicCHF and arterial hypertension (AH). Torsemide is similar to other loopdiuretics in terms of its mechanism of diuretic action. It has higherbioavailability (about 80%) and a longer elimination half-life (3 to 4hours) than furosemide. In the treatment of CHF Torsemide (5 to 20mg/day) has been shown to be an effective diuretic. Non-diuretic dosages(2.5 to 5 mg/day) of Torsemide have been used to treat essential AH,both as monotherapy and in combination with other antihypertensiveagents (e.g. calcium channel blocker, ACE inhibitors, ARBs, diuretics,and alpha and/or beta blockers). When used in these dosages, Torsemidelowers diastolic blood pressure to below 90 mm Hg in 70 to 80% ofpatients. Antihypertensive efficacy of Torsemide is similar to that ofthiazides and related compounds. Thus low-dose Torsemide constitutes analternative to thiazides diuretics in the treatment of essential AH.

Torsemide also appears to have additional actions beyond a pure diureticeffect, such as an anti-aldosterone effect and vaso-relaxation effect.These effects of Torsemide are mediated via several biological pathwaysincluding but not limited to modulation of renin-angiotensin-aldosteronesystem (RAAS), modulation of guanylyl cyclase activity, modulation ofsecretion of brain natriuretic peptide and atrial natriuretic factor,modulation of mineralocorticoid receptors, collagen/collagen type I, andmyocardial fibrosis. All of these effects of Torsemide are dependent andconcentration and duration of Torsemide bioavailability. The extendedrelease Torsemide formulations described here maintain Torsemidebioavailability for longer duration as compared to the immediate releaseTorsemide and thereby differentially modulate above biological pathways.Moreover, studies have also investigated whether the superiorpharmacokinetics and pharmacological activity of Torsemide result in afavorable clinical outcome. Their results have indicated that, incomparison with furosemide, Torsemide improves left ventricularfunction, reduces mortality as well as the frequency and duration ofheart failure-related hospitalization, and improves quality of life,exercise tolerance and NYHA functional class in patients with congestiveheart failure. Thus, Torsemide appears to be a promising loop diureticthat contributes to better management of patients with heart failure.

Torsemide is a high-ceiling loop diuretic, which acts on the thickascending limb of the loop of Henle to promote rapid and markedexcretion of water, sodium and chloride. Like furosemide, its major siteof action is from the luminal side of the cell. Torsemide is at leasttwice as potent as furosemide on a weight-for-weight basis, producesequivalent diuresis and natriuresis at lower urinary concentrations andhas a longer duration of action, allowing once-daily administrationwithout the paradoxical antidiuresis seen with furosemide. Torsemidealso appears to promote excretion of potassium and calcium to a lesserextent than furosemide. In trials of up to 48-week duration in patientswith mild to moderate essential hypertension, Torsemide, administered asa single daily dose, has been shown to achieve adequate blood pressurecontrol reaching steady-state within 8 to 12 weeks. Those patients notresponding initially have generally responded to a doubling of the dose.Comparative trials of up to 6 months show Torsemide is as effective asindapamide, hydrochlorothiazide or a combination oftriamterene/hydrochlorothiazide in maintaining control of bloodpressure. Torsemide has also been used successfully to treat edematousstates associated with chronic congestive heart failure, renal diseaseand hepatic cirrhosis. In short term trials control of blood pressure,bodyweight and residual edema has been sustained. Torsemide appears tobe a useful alternative to furosemide in these patients, providingpotent and long-lasting diuresis while being relatively potassium andcalcium sparing. In clinical trials to date Torsemide has been welltolerated with adverse effects of a mild, transient nature reported byonly small numbers of patients. Changes in biochemical parameters havebeen common, including decreases in plasma sodium and potassium levelsand increases in plasma creatinine and uric acid levels. These changesare typical of loop diuretics. No changes were clinically significantnor were clinically relevant changes noted in glucose metabolism,cholesterol or triglyceride levels or in hematological values. Thus,Torsemide is an interesting new loop diuretic with potential use in thetreatment of mild to moderate essential hypertension and of edematousstates in which diuretic therapy is warranted. Preliminary studiessuggest it to be as efficacious as other diuretics in common use and tohave some advantage over furosemide in duration of action and in effectson potassium and calcium.

CHF is the cause of significant mortality all over the world and itsincidence and prevalence are increasing. Fluid retention and volumeoverload are responsible in large part of morbidity related to heartfailure. Torsemide is the only loop diuretic for which it has been shownto effectively lower high blood pressure even with low doses. Inaddition, Torsemide is a very safe drug. In a post marketingsurveillance study (TORIC) of 1,377 patients with CHF, Torsemidesignificantly reduced cardiovascular mortality in comparison tofurosemide; see Ishido et al., Torsemide for the treatment of heartfailure. Cardiovasc. Hematol. Disord. Drug Targets. 2008 June;8(2):127-32. Review, herein incorporated by reference in its entirety.In a recent study, Torsemide reversed myocardial fibrosis and reducedcollagen type I synthesis, improving cardiac remodeling in patients withCHF; see Preobrazhenskii et al., Torsemide is the effective loopdiuretic for long-term therapy of arterial hypertension. Kardiologiia.2011; 51(4):67-73. Review, herein incorporated by reference in itsentirety.

More than 20 million people in the U.S. have Chronic Kidney Disease(CKD). Over half a million people are treated annually for End-StageRenal Disease (ESRD). In patients with advanced renal failure, highdoses of loop diuretics are required to promote negative sodium andwater balance and to treat hypertension. Torsemide is a new loopdiuretic that has a high bioavailability of 80% and a plasma half-lifeof 3-5 hours, which remains unchanged in chronic renal failure. Even inpatients with advanced renal failure, intravenous and oral high-doseTorsemide proves effective in increasing fluid and sodium excretion in adose-dependent manner. A number of studies in renal failure patientsprovide evidence that, on a weight-by-weight basis, the ratio ofdiuretic potency between Torsemide and furosemide is 1:2.5 after oraldosing and 1:1 after intravenous administration.

However, common problems with diuretics are acute and chronic tolerance.Acute tolerance occurs in a breaking phenomenon associated with a shiftto the right of the dose response curve and occurs after initial dosing.Chronic tolerance occurs after 5-10 weeks of dosing and is associatedwith tubular hypertrophy and sodium rebound phenomena. Although multiplephysiological mechanisms are involved in this phenomenon, acute volumedepletion is the main stimulus to this phenomenon.

Oral controlled-release (CR, e.g., extended-release (ER) orprolonged-release (PR)) formulations overcome many of the drawbacks ofconventional immediate release (IR) dosage forms.

For example, FIG. 1 shows observed and model-predicted plasmaconcentration of Torsemide after administration of a 20 mgimmediate-release (IR) formulation. As can be seen, the plasmaconcentration peaks within 1 hour of administration and theconcentration decreases thereafter. This may lead to alternating periodsof toxic levels and sub-therapeutic concentrations, and therebydecreasing the therapeutic efficacy and inviting toxic side effects.

Contrary to IR dosage forms, CR tablets are not associated withalternating periods of toxic levels and sub-therapeutic concentrations,and thereby improving the therapeutic efficacy and avoiding toxic sideeffects. Therefore, CR has certain distinct advantages such as (1)reduction in drug plasma level fluctuation with maintenance of a steadyplasma level of the drug over a prolonged time period, ideallysimulating an intravenous infusion of a drug; (2) reduction in adverseside effects and improvement in tolerability, as drug plasma levels aremaintained with in a narrow window with no sharp peaks and with AUC ofplasma concentration versus time curve comparable with total AUC frommultiple dosing with immediate release dosage forms; (3) patient comfortand compliance, as oral drug delivery is the most common and convenientfor patients, and a reduction in dosing frequency enhances compliance;(4) reduction in healthcare cost, as the total cost of therapy of thecontrolled release product could be comparable or lower than theimmediate release product. With reduction in side effects, the overallexpense in disease management also would be reduced, this greatlyreduces the possibility of side effects, as the scale of side effectsincrease as we approach the maximum safe concentration; and (5) avoidnight time dosing, as it is also good for patients to avoid the dosingat night time.

Controlled release products can be classified as follows: (1) reservoirsystems including enteric coated products; (2) osmotic systems; (3)ion-exchange resins; and (4) matrix systems. Matrix systems can furtherbe subdivided into (a) monolithic matrix tablets; (b) erodible(hydrophobic) matrix tablets; and (c) gel forming hydrophilic matrictablets

Most monolithic matrix tablets use inert matrix, which does not interact(inert) with biological fluids. The main reason for popularity of thissystem is drug release from the matrix is independent of the states andcondition of digestive juices, which shows quite large inter- andintra-patients variability. Nowadays, research in this area focuses onnatural biopolymers such as cellulose and starch derivatives, some ofwhich could be considered semi-inert (e.g. ethylcellulose).

Gel-forming hydrophilic or swellable matrix systems are homogeneous orheterogeneous systems in which the drug is dispersed in a swellablehydrophilic polymer. The drug release is a function of polymercharacteristics. Most widely studies gel-forming polymer in controlledrelease is poly(hydroxyethyl methacrylate (pHEMA). Because of theirswelling capacity, several cellulose derivatives are applied as swellinggel-forming controlled release drug delivery excipients and most widelyused is hydroxypropylmethyl-cellulose (HPMC). However, a variety ofdifferent molecular weight HPMC are available and they vary in theirrelease characteristics. Specifically, viscosity and erosion/dissolutioncharacteristic of gel layer varies greatly and allows manipulations withexpected drug released profile.

Other swellable polymers used in matrix tablets are natural orartificial gum, and dextrans.

Erodible polymers such as polyanhydrides provide for other types ofexcipients for controlled release drug with zero-order profile.

U.S. Patent Publication No. 2003/0152622 A1, herein incorporated byreference in its entirety, describes formulations of an erodible gastricretentive oral diuretic, and exemplifies furosemide as the diuretic.

U.S. Patent Publication No. 2007/0196482 A1, herein incorporated byreference in its entirety, describes a sustained release oral dosageform using gum-based gelling gum such as xanthan and locust bean gums.

Moreover, a group in Spain has developed a prolonged-release (PR)Torsemide; see Diez et al., TORAFIC study protocol: Torsemide prolongedrelease versus furosemide in patients with chronic heart failure. ExpertRev Cardiovasc Ther. 2009 August; 7(8):897-904, herein incorporated byreference in its entirety.

Biologically, PR Torsemide was found to be similar in systemic exposurebut significantly slower rates of absorption and lower fluctuations inplasma concentrations. Its natriuretic efficiency is higher and diuresisis more constant, with a better tolerability.

However, both the controlled release drug claimed in 2003/0152622-A1 and2007/0196482-A1 applications, both herein incorporated by reference intheir entireties, failed to achieve desired effect sin clinicaldevelopments. Additionally, the Spanish version of PR Torsemide showsonly a modest release profile of about 5-6 hours.

Therefore, in view of the above, there exists a need in the art forimproving the effectiveness of diuretic therapy via better-sustained(e.g., extended) release loop diuretic such as Torsemide.

SUMMARY OF THE INVENTION

In an aspect, the invention provides an extended-release oral dosageformulation, such as a tablet, comprising a therapeutically effectiveamount of Torsemide or a pharmaceutically acceptable salt thereof and atleast one matrix component, wherein the at least one matrix component isselected from the group consisting of: hydroxy propyl cellulose (HPC),hydroxpropyl methyl cellulose (HPMC), glyceryl behenate, and apolyethylene glycol glyceride. In an aspect, Torsemide is present in theformulation in a range of about 1 wt % to about 20 wt %, or about 5 wt %to about 10 wt % and the matrix component is present in the formulationin a range of about 5 wt % to about 50 wt %, or about 15 wt % to about35 wt %.

In an aspect, the extended-release oral dosage formulation may compriseabout 5 wt % to about 10 wt % of Torsemide or a pharmaceuticallyacceptable salt thereof; about 10 wt % to about 40 wt % of a matrixcomponent; about 50 wt % to about 60 wt % of at least one binder; about5 wt % to about 15 wt % of lactose; about 1 wt % to about 3 wt % oftalc; and about 0.5 wt % to about 1 wt % of magnesium stearate.

In another aspect, an extended-release oral dosage formulation mayfurther comprise at least one binder, lactose, talc and magnesiumstearate is provided, wherein the at least one binder present is amicrocrystalline cellulose binder and is present in the formulation in arange of about 25 wt % to about 75 wt %, lactose is present in theformulation in a range of about 1 wt % to about 20 wt %, talc is presentin the formulation in a range of about 1 wt % to about 5 wt %, andmagnesium stearate is present in the formulation in a range of about 0.1wt % to about 2 wt %.

In yet another aspect, the extended-release oral dosage formulation maybe combined with and/or comprise at least one of an ACE inhibitor, analdosterone receptor antagonist, a calcium channel blocker, a thiazidediuretic, an angiotensin receptor blocker, an alpha blocker,potassium-sparing diuretic (e.g. Amiloride), central sympatheticsuppressant (e.g. Moxonidine, Rilmenidine, Clonidine), and abeta-blocker, the ACE inhibitor is selected from the group consistingof: alacepril, benazepril, captopril, cilazapril, delapril, enalapril,enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril,perindopril, quinapril, ramipril saralasin acetate, temocapril,trandolapril, ceranapril, moexipril, quinaprilat and spirapril.

In yet another aspect, a method of making an extended-release oraldosage formulation comprising Torsemide may comprise forming a mixturecomprising at least Torsemide and a matrix component; wet granulatingthe mixture to form particles; sizing the particles; and forming theextended-release oral dosage formulation.

In a further aspect, a method of using the extended-release oral dosageformulation comprising Torsemide may comprise administering atherapeutically effective amount of the formulation to a subject in needthereof. In a further aspect, a method of mitigating the reduction of anamount of GFR and/or increasing an amount of GFR may compriseadministration of a therapeutically effective amount of the Torsemide ERformulations described herein to a patient in need thereof. In a furtheraspect, a method of increasing fluid and/or Na⁺ loss may compriseadministration of a therapeutically effective amount of the Torsemide ERformulations described herein to a patient in need thereof.

In yet a further aspect, administration of the extended-release oraldosage formulation comprising Torsemide leads to a novel mechanism forTorsemide action in diuresis by acting on Na⁺/K⁺/2Cl⁻ co-transporter inthe kidney and/or acting on guanylate cyclase (GC), specificallymembrane bound GC and modulated actions of peptide hormones such asbrain natriuretic peptide (BNP) and atrial natriuretic peptide.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows observed (mean±standard error) and model-predictedTorsemide plasma concentrations after administration of a 20 mg IRformulation.

FIG. 2 shows model-predicted Torsemide plasma concentrations afteradministration of 20 mg IR and ER formulations.

FIG. 3 shows model-predicted urinary Torsemide excretion rates afteradministration of 20 mg IR and ER formulations.

FIG. 4 shows model-predicted urinary sodium excretion rates afteradministration of 20 mg IR and ER formulations.

FIG. 5 shows observed and model-predicted percent dissolution ofTorsemide from an ER oral dosage formulation.

FIG. 6 shows Mean±SEM values (n=10 per group) for subjects receiving 20mg of Torsemide as the IR preparation (continuous lines) or ER (dashedlines) as a function of time after Torsemide administration. FIG. 6Ashows urine flow; FIG. 6B shows creatinine clearance; FIG. 6C showssodium excretion; FIG. 6D shows potassium excretion. The mean values forthe previous 24 hours are indicated by the horizontal dotted lines.

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more fully hereinafter withreference to the accompanying figures, in which embodiments of theinvention are shown. This invention may, however, be embodied in manyalternate forms and should not be construed as limited to theembodiments set forth herein.

Modeling studies have shown that ER Torsemide may provide an improveddiuretic therapy over IR Torsemide, particularly using acontrolled-release loop diuretic. The molecular structure of Torsemideis shown below.

ER formulations comprising Torsemide may comprise, as acontrolled-release agent, a matrix based on erosion-controlled polymersand/or a matrix based on lipids and fatty acids.

Erosion Controlled Polymer Based Matrix Tablet Formulations

Matrix technologies based on hydrophilic polymers have proven popularamong the oral controlled drug delivery technologies because of theirsimplicity, ease in manufacturing, high level of reproducibility,stability of raw materials and dosage forms, ease of scale-up andprocess validation. Due to these advantages, the matrix tablet platformmay be used for Torsemide ER formulations.

Polymers with varying chemistry/molecular weights, for example HydroxyPropyl Cellulose (HPC), Hydroxpropyl methyl cellulose (HPMC) may be usedso as to target the drug release from the matrix independent of pH.Torsemide may be mixed with polymers and other excipients, this mixturemay then be wet granulated, dried and sized, then compressed into tabletform. The polymer may be added into the formulation in the concentrationbetween about 5% and about 50% based on the total tablet weight,preferably between about 10% and about 40%, and more preferably betweenabout 15% and about 35% based on the total tablet weight. If required,pore formers may be added into the formulation to facilitate drugdiffusion from the matrix. Since the solubility of Torsemide is low inwater, medium and low molecular weight polymers may be used forgranulation.

Lipid and Fatty Acid Based Tablet Formulations

Lipid excipients may be utilized to deliver clinically relevantsustained drug release profiles (8, 12, 24 hours) through the creationof an insoluble matrix structure from which diffusion is the principaldrug extended-release mechanism.

Many lipid and fatty acid based excipients may be used as a releasecontrolling agent. A few of the excipients such as glyceryl behenate(e.g. Compritol) and polyethylene glycol glyceride (e.g. Gelucire) maybe used for the development of ER tablets. These lipid excipientsproduce ER release tablet matrices with pH independent release kinetics.These tablets may be made using simple techniques that yield highlystable drug release profiles. Drug release profile may be modulated bythe addition of hydrophilic diluents like lactose or water-insolublediluents depending on the desired kinetics and tablet characteristics. Atarget profile as described in Table 1 may be used as reference.

TABLE 1 Target Profile Release Percentage. Target Profile Time in HrTorsemide Release in % 1 Hr 15-21 4 Hr 50-65 8 Hr 65-75 12 Hr  80-95

The oral dosage ER Torsemide formulation may comprise Torsemide in arange of about 1 wt % to about 20 wt %. More preferably, the Torsemidemay be present in a range of about 5 wt % to about 10 wt %. Mostpreferably, the Torsemide may be present in a range of about 6 wt % toabout 7 wt %. Alternatively, the oral dosage ER Torsemide formulationmay comprise Torsemide in a range of about 5 mg to about 50 mg. Morepreferably, the Torsemide may be present in a range of about 10 mg toabout 40 mg or about 20 mg to about 30 mg. Most preferably, theformulation comprises 20 mg of Torsemide.

The matrix component (e.g., erosion-controlled polymer and/orlipid/fatty acid) may be comprised in the oral dosage formulation in arange of about 1 wt % to about 50 wt %. More preferably, the matrixcomponent may be present in a range of about 10 wt % to about 40 wt %.Most preferably, the matrix component may be present in a range of about15 wt % to about 35 wt %. Alternatively, the oral dosage ER Torsemideformulation may comprise the matrix component in a range of about 10 mgto about 90 mg. More preferably, the matrix component may be present ina range of about 20 mg to about 70 mg or about 30 mg to about 50 mg.

The ER oral dosage formulations may also comprise other ingredients,such as a binder or binders, lactose, talc and magnesium stearate.

The binder may be comprised in the oral dosage formulation as a singlebinder or a plurality of binders, for example a primary binder (e.g., bywt %) and a secondary binder, or binders. The primary binder may be acellulose binder, and is preferably a microcrystalline cellulose bindersuch as Avicel PH 302, Avicel PH 101 and/or Avicel PH 102. The primarybinder may be present in the oral dosage ER formulation in a range ofabout 25 wt % to about 75 wt %. More preferably, the primary binder maybe present in a range of about 50 wt % to about 60 wt %. Mostpreferably, the primary binder may be present in a range of about 50 wt% to about 57 wt %. Alternatively, the oral dosage ER Torsemideformulation may comprise the primary binder in a range of about 50 mg toabout 200 mg. More preferably, the primary binder may be present in arange of about 60 mg to about 150 mg or about 80 mg to about 100 mg.

Secondary binders, such as a polyvinylpyrrolidone (e.g., PVP K 30), mayalso be included in smaller wt % ranges, such as about 1 wt % to about10 wt %, or more preferably 3 wt % to about 9 wt %. Alternatively, theoral dosage ER Torsemide formulation may comprise the secondary binderin a range of about 1 mg to about 20 mg. More preferably, the secondarybinder may be present in a range of about 5 mg to about 15 mg.

Lactose may be present in the oral dosage ER formulation in a range ofabout 1 wt % to about 20 wt %. More preferably, lactose may be presentin a range of about 5 wt % to about 15 wt %. Most preferably, lactosemay be present in a range of about 8 wt % to about 14 wt %.Alternatively, the oral dosage ER Torsemide formulation may compriselactose in a range of about 5 mg to about 50 mg. More preferably,lactose may be present in a range of about 10 mg to about 25 mg.

Talc and magnesium stearate may be present in the oral dosage ERformulation. Talc may be present in a range of about 1 wt % to about 5wt %. More preferably, talc may be present in a range of about 1 wt % toabout 3 wt %. Alternatively, the oral dosage ER Torsemide formulationmay comprise talc in a range of about 1 mg to about 10 mg. Morepreferably, talc may be present in a range of about 2 mg to about 5 mg.

Magnesium stearate may be present in a range of about 0.1 wt % to about2 wt %. More preferably, magnesium stearate may be present in a range ofabout 0.5 wt % to about 1 wt %. Alternatively, the oral dosage ERTorsemide formulation may comprise magnesium stearate in a range ofabout 0.5 mg to about 5 mg. More preferably, magnesium stearate may bepresent in a range of about 1 mg to about 2 mg.

The ER oral dosage Torsemide formulation may be used alone or incombination with other therapeutic agents such as, without limitation,ACE inhibitors, calcium channel blockers such as amlodipine, thiazidediuretics, angiotensin receptor blockers (ARBs) and alpha andbeta-blockers. The other therapeutic agents may be administered with theER Torsemide either sequentially or simultaneously. If administeredsimultaneously, a single capsule having a fixed ratio of the activeagents may be used. If administered sequentially, the active agents maybe used in multiple, separate capsules.

A combination therapy may comprise three active agents, such as an ACEinhibitor, an aldosterone receptor antagonist and a loop diuretic. Forthe ACE inhibitor and a loop diuretic combination, the formulations maycomprise a weight ratio range from about 0.5% to about 1% based on thetotal tablet weight. These same agents may be present in theformulations in ratios of about 20:1 of the ACE inhibitor to the loopdiuretic.

Examples of ACE inhibitor, which may be used in the combination therapy,may be selected from the group consisting of: alacepril, benazepril,captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril,fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramiprilsaralasin acetate, temocapril, trandolapril, ceranapril, moexipril,quinaprilat and spirapril.

Methods of making the ER oral dosage Torsemide formulations describedherein are not particularly limited and may comprise: forming a mixturecomprising Torsemide, a matrix component and other ingredients,granulating (e.g., wet granulating) the mixture to form particles,drying the particles, sizing the particles and forming an oral dosagecontrolled-release formulation, such as a tablet.

Methods of using the ER oral dosage Torsemide formulations describedherein to treat the aforementioned conditions and diseases are also notparticularly limited and may comprise administering a therapeuticallyeffective amount of Torsemide to a subject in need thereof.

In-Vitro Studies Example 1

In-vitro studies using Torsemide ER formulations were carried out andseveral ER formulations were used, including those based on anerosion-controlled, polymer-based matrix and a lipid/fatty acid basedmatrix.

For erosion-controlled, polymer-based matrix tablet formulations,Hydroxy Propyl Cellulose (HPC) was used as a controlled-release agent.Details of the release profile obtained from in-vitro stability studiesare shown in Table 2 below.

TABLE 2 Release Profiles for ER Torsemide using HPC. B.No. B.No. B.No.B.No. B.No. Ingredients 11-173- 11-173- 11-173- 11-173- 11-173- S.No.(mg) 01 03 04 05 07 1 Torsemide 10 10 10 10 10 2 Avicel PH 302 84 98 10091 92 3 HPC HXF PH 51 50 47 50 45 4 Lactose — 14 15 21 25 (Super Tab) 5Talc 4 2 2 2 2 6 Mag-Stearate 1 1 1 1 1 150 175 175 175 175

Details of in-vitro dissolution testing results are shown in Table 3below.

TABLE 3 In-Vitro Dissolution Testing Results Target B.No. B.No. B.No.B.No. B.No. Time Release 11-173- 11-173- 11-173- 11-173- 11-173- in HrProfile 01 03 04 05 07 1 hr 18 16.8 21.9 23.4 22.9 27.3 2 hr 30 25.233.1 34.6 34.8 39.9 3 hr 40 31.7 41.3 42.9 42.7 49.0 4 hr 52 37.2 47.849.4 49.5 56.5 6 hr 60 46.6 57.9 59.3 59.8 67.4 8 hr 70 54.1 65.6 66.766.8 74.8 10 hr 80 60.7 71.5 72.2 72.5 79.8 12 hr 90 66.0 76.1 76.2 76.282.8

For lipid and fatty acid based matrix tablet formulations, Compritol 888was used as a lipid matrix. Details of the release profile obtained fromin-vitro testing are shown in Table 4 below.

TABLE 4 Release Profiles for ER Torsemide using HPC. B. No. B. No. S.No. Ingredients 11-173-02 11-173-06 1 Torsemide 10 10 2 Avicel PH 102 93— 3 Avicel PH 101 — 87 4 Compritol 888 34 31 5 Lactose Super Tab 30GR 2025 6 PVP K 30 6 15 7 Talc 5 5 8 Mag-Stearate 2 2 Tablet Weight 170 175

Details of in-vitro dissolution testing results are shown in Table 5below.

TABLE 5 In-Vitro Dissolution Testing Results Time Target Release B. No.B. No. in Hr Profile 11-173-02 11-173-06 1 hr 18 16.2 17.3 2 hr 30 25.327.2 3 hr 40 33.9 35.6 4 hr 52 43.3 43.5 6 hr 60 60.1 56.1 8 hr 70 70.965.2 10 hr 80 78.6 72.4 12 hr 90 84.6 77.7

Accordingly, the data listed in Tables 1-5 was used as a basis for themodeling curves shown in FIGS. 1-4 and part of FIG. 5.

FIG. 1 shows modeling of Torsemide plasma concentrations afteradministration of 20 mg IR and ER formulations. As can be seen, the ERformulation had a higher concentration of Torsemide 4 hours afteradministration than did the IR formulation.

FIG. 2 shows modeling of urinary Torsemide excretion rates of Torsemideafter administration of 20 mg IR and ER formulations. As can be seen,much of the Torsemide of the IR formulation has been excreted within 4hours of administration, whereas much less of the Torsemide of the ERformulation was excreted in the same time period.

FIG. 3 shows modeling of urinary Torsemide excretion rates of Torsemideafter administration of 20 mg IR and ER formulations. As can be seen,much of the Torsemide of the IR formulation has been excreted within 4hours of administration, whereas much less of the Torsemide of the ERformulation was excreted in the same time period.

FIG. 4 shows modeling of Na⁺ excretion rates after administration of 20mg IR and ER formulations. As can be seen, much of the Na⁺ of the IRformulation has been excreted within 4 hours of administration, whereasmuch less of the Na⁺ of the ER formulation was excreted in the same timeperiod.

FIG. 5 shows observed and model-predicted percent dissolution ofTorsemide from an ER oral dosage formulation. As can be seen, themodel-predicted data closely matches that of the experimentally observeddata.

Example 2

In-vivo studies comparing Torsemide IR (Demadex Rx) with anextended-release (ER) formulation prepared by Sarfez, Inc.

Subjects:

Ten normal volunteers, aged 21 to 73 years were recruited. They had nosignificant past medical history, were not taking medications, and hadnormal values for blood urea nitrogen, serum creatinine, plasmaelectrolytes, liver function tests, hemogram, and urinalysis. All had ablood pressure less than 140/90 mmHg. Their body weights were 61.2 and73.0 kg.

Trial Design:

Each subject received both of the Torsemide preparations in a randomizedcrossover design separated by a 3-week washout period. Subjects werepre-consented, admitted, and received a fixed constant diet for 3 dayscontaining 300 mmol per day sodium and 45 mmol per day of potassium.This was verified by ashing and analyzing the food items fed to thesubjects. Throughout the 3 days, subjects remained in the metabolicward. Each meal was observed to ensure that subjects ate all the foodgiven to them. Subjects remained within the facility for the duration ofthe study. No visitors were allowed. This provided strict control offood, sodium, and potassium intakes. Fluid was allowed ad libitum.During day 2, subjects collected a 24-hour urine. Thereafter, there wasa 2-hour period during which the subjects were prepared for theprocedures on the experimental day. They were weighed, an intravenouscannula inserted, and blood pressure and heart rate taken using anautomated device after 2 minutes of sitting. They were fasted for 12hours prior to receiving the drug, and for 4 hours thereafter. Tocompensate for loss of salt intake (50 mmol of Na⁺) during the breakfastperiod, they received 233 mL of 0.154 M saline solution immediatelyprior to drug administration. At zero time, they received 20 mg ofTorsemide (IR or ER) with 300 mL of water. Immediately before ingestion,and for 23 hours thereafter, blood and urine samples were taken atdesignated times and another 24-hour urine was collected. Aftercompletion of the study, subjects were weighed, blood pressure and heartrate were recorded in the sitting position and they were discharged.

Analyses:

Urine samples were measured for volume and aliquots taken. Na⁺ and K⁺concentrations were measured in an automated apparatus with an ionselective electrode, and creatinine concentrations in a creatinineanalyzer. Other aliquots were saved for measurement of Torsemide. A 35ml blood sample was taken immediately prior to, and an 8 hour and 23hours after the drug administration. This was analyzed for creatinineand for key hormones including plasma renin activity (PRA), serumaldosterone concentration (SAC), and brain natriuretic peptide (BNP).

Statistics:

Mean±SEM data were calculated for each drug period in each individualsubject. Within subject paired t-tests were used to assess differencesin response to the IR versus DR preparations. A P value <0.05 were takenas statistically significant.

Results:

All 10 subjects completed both arms of the trial without any adverseeffects. The patterns of urine flow, creatinine clearance, sodium andpotassium excretion following drug administration are shown in FIG. 6.The average values for the prior 24-hours are indicated by horizontaldotted lines. Urine flow increased rapidly with the IR preparation andwas significantly greater than ER for the first hour (FIG. 6A). Bothpreparations achieved a similar maximal urine flow rate of circa 15mL·min⁻¹. By 3 hours, urine flow was significantly greater with ER thanIR and remained so until 12 hours.

There was an initial sharp increase in creatinine clearance during thefirst ½ hr after administration of both formulations of Torsemide (FIG.6B), but this returned abruptly to baseline and was reduced belowbaseline at 2 hours where it remained during most of the period from2-23 hours. There were no significant differences in creatinineclearance between IR and ER during these periods.

Sodium excretion increased rapidly with the IR preparation to a maximumof 1.6 mmol per minute by 1.0 to 1.5 hr (FIG. 6C). Thereafter, rates ofNa⁺ excretion with the IR and ER preparation were similar until 3 hourswhen Na⁺ excretion was greater with ER. This difference remained until12 hours.

Potassium excretion increased sharply with both preparations andremained elevated for about 4 hr (FIG. 6D). K⁺ excretion was greaterwith IR from 1-1.5 hours and with ER from 3-4 hours, but generallyfollowed a similar pattern. After 12 hours, K⁺ excretion was low in bothgroups.

The individual values for excretion and creatinine clearance for the24-hour period immediately before and for 24-hour immediately after drugadministration demonstrates that fluid excretion was not significantlychanged after IR, but was increased significantly after ER resulting ina significantly 2.2-fold greater fluid loss of 906 mL after ER versus IR(data not shown). The creatinine clearance was significantly reduced by25% following IR, but was not significantly changed following ER (datanot shown). Sodium excretion was increased significantly after bothdrugs, but the increased was significantly greater by 2.2-fold after ER(data not shown). Neither drug changed 24 hour potassium excretion.

Fluid excretion, Ccr, Na⁺, K⁺ excretion, FENa and FEK were notsignificantly different before administration of IR vs. ER (data notshown). A major difference between the responses to the two formulationsis the greater loss of fluid and Na⁺ after ER vs. IR. The GFR tended tofall after Torsemide (significant only for IR). The greater increasedexcretion of Na⁺ after ER vs. IR was matched by a lesser reduction inGFR (and hence a better preserved filtered load of Na⁺). The outcome wasthat there was a similar increase in fractional excretion of sodium(FENa) after IR and ER. Both formulations tended to increase K⁺excretion (not significant for either). The outcome of a rather higherK⁺ excretion with a rather lower GFR (and hence a reduced filtered loadof K⁺) was a consistent increase in fractional excretion of potassium(FEK) that was similar for both formulations (data not shown).

The body weight, blood pressure, heart rate and plasma data (data notshown) demonstrates that body weight decreased significantly only afterER. The diastolic blood pressure was increased after IR, but tended tofall after ER, resulting in a significantly greater reduction indiastolic and mean blood pressures after ER compared to IR. Heart ratewas reduced after both formulations. There were similar increases inserum creatinine but no significant changes in serum sodium or potassiumconcentrations.

The pharmacokinetic data are shown in Table 6. Compared to IR, theC_(MAX) with ER was reduced 69% and the AUC was reduced 18-21%. TheT_(MAX) was prolonged 2.5-fold with a 59% reduction in AUC from 1 to 3hours but a 97% increase in AUC from 8-10 hours. The Kel was reduced 32%resulting in a 45% increase in t1/2. The apparent V_(D) was increased79%. All of these differences were statistically significant.

TABLE 6 Pharmacokinetic Parameters after Administration of Torsemide:for Immediate Release and Delayed Release Formulations. Fold differ- PParameter IR DR ence value C_(max) (ng · ml⁻¹) 2962 ± 412 905 ± 93 −69<0.001 AUC_(0-t) (hr*/ng · ml⁻¹) 6493 ± 688 5125 ± 552 −21 <0.001AUC_(0-inf) 6728 ± 704 5543 ± 565 −18 <0.001 (hr*/ng · ml⁻¹) T_(max)(hr)  1.03 ± 0.13  3.53 ± 0.27 +243 <0.001 AUC₁₋₃ (hr*/ng · ml⁻¹) 2966 ±294 1225 ± 161 −59 AUC₈₋₁₀ 203 ± 32 400 ± 50 +97 (hr*/ng · ml⁻¹) Kel(hr) 0.266 ± 0.03 0.194 ± 0.03 −32 t_(1/2) (hr)  2.81 ± 0.25  4.07 ±0.57 +45 V_(D) (ml) 2498 ± 789 22414 ± 3139 +79 Mean ± Sem values (n =10 per group)

The main findings from this study are that a novel ER formulation ofTorsemide that delivered the drug into solution over 12 hours led to amore prolonged period of natriuresis and diuresis and a two-fold largerloss of fluid and Na⁺ than a traditional IR formulation. This resultedin a significant loss in body weight and a significantly greaterreduction in diastolic and mean blood pressures. The C_(cr) was reducedonly after the IR preparation, which reduces the filtered load of Na⁺.The combination of a greater loss of Na⁺, but a better preservedfiltered load of Na⁺ after the ER compared to the IR formulationresulted in similar increases in FENa. For both drugs, a period ofdiuresis, natriuresis and kaliuresis was followed by sustained renalfluid and electrolyte retention. Neither drug led to a significant lossof potassium but again the lower levels of GFR reduced the filtered loadof K⁺ and led to significant, and similar, increases in FEK with bothformulations. The ER formulation prolonged the time to maximal plasmaTorsemide concentration by 2·5 fold with a corresponding reduction inTorsemide plasma levels 1 to 3 hours after dosing, but a doubling ofplasma levels 8-10 hours after dosing. The overall bioavailability wasreduced by 18%. The combination of an enhanced Na⁺ loss despite areduced bioavailability implies that the ER formulation had increasedthe diuretic efficiency.

The daily intake of Na⁺ in this study of 300 mmol was designed to matchprior studies in normal subjects given furosemide. The IR formulation ofTorsemide (20 mg) did not increase fluid excretion or weight loss over24 hours but led to a modest, but significant, Na⁺ loss of 42 mmol.

Torsemide ER led to a similar maximal naturesis as IR, but the peak wasdelayed by about 1 hour. The main effect of the ER preparation was toprolong the period of Na⁺ and fluid loss (relative to the IR) by 4 fold.This led to a significantly greater fluid and Na⁺ loss with the ERformulation. These greater salt and water depleting actions of TorsemideER were accompanied by significant reductions in body weight only afterER and by significantly greater reductions in diastolic and mean bloodpressure after ER.

Therefore, the present findings that a ER formulation of Torsemide ledto significantly more Na⁺ and fluid loss than an IR preparation and thatonly the ER preparation increased fluid excretion and reduced bodyweight and diastolic blood pressure, carries clinical impact since thesestudies were conducted at a high level of salt intake. They raise thepossibility that dietary salt restriction may not be absolutely requiredto achieve predictable salt and water loss and a reduction in bloodpressure during treatment of patients with hypertension or CHF with ERTorsemide.

This study supports the hypothesis that a more prolonged duration ofloop diuretic action enhances fluid and Na⁺ loss. This study alsoconfirms the hypothesis that a more prolonged duration of action of aloop diuretic would prolong the sojourn of plasma levels in the mostefficient 25-70% of maximal range and in an improvement in overallnatuiretic efficiency.

The regulation of GFR by loop diuretics is complicated and unresolved.Two factors have been identified that may increase the measured GFR.There is an artifactual initial increase caused by flushing out ofconcentrated GFR markers from the tubules by the abrupt increase inurine flow, as seen in the first 30 minutes of this study (FIG. 6B).Second, inhibition of tubuloglomerular feedback would reduce afferentarteriolar resistance and should increase the GFR. Three factors havebeen identified that may reduce the GFR. Inhibition of fluidreabsorption raises the intertubular pressure substantially, which willlimit the force for glomerular filtration. Second, the release ofvasoactive agents could reduce the renal blood flow. Third, depletion ofbody fluid can cause renal vasoconstriction. The present studydemonstrated that, after the early (artifactual) increase in GFR, therewas a rapid return to baseline and below resulting in a significant 25%reduction in creatinine clearance in the 24 hours after Torsemide IR.This constitutes a serious adverse effect since even modest reductionsin GFR, especially when accompanied by release of vasoactive hormones,increases the risk of CVD and limit antihypertensive and fluid-depletingefficacy.

Thus, these results demonstrate that an ER formulation of Torsemideincreased fluid and Na⁺ loss and mitigated significant reductions inGFR, compared to the IR formulation. Thus, a method of mitigating thereduction in GFR and/or the increase in GFR may comprise administrationof a therapeutically effective amount of the Torsemide ER formulationsdescribed herein to a patient in need thereof. Also, a method ofincreasing fluid and/or Na⁺ loss may comprise administration of atherapeutically effective amount of the Torsemide ER formulationsdescribed herein to a patient in need thereof.

It has also been surprisingly found that the Torsemide ER formulationsdescribed herein, when administered, lead to a novel mechanism forTorsemide action in diuresis. It is known that torsemide acts onNa⁺/K⁺/2Cl⁻ co-transporter in the kidney. It has been found thatTorsemide also interacts with guanylate cyclase (GC), specificallymembrane bound GC (mGC) and modulated actions of peptide hormones suchas brain natriuretic peptide (BNP) and atrial natriuretic peptide.Structurally, torsemide is similar to atrial natriuretic peptide (ANP)and can compete for binding to its receptor. However, other members ofthe loop diuretic class such as furosemide cannot compete with ANP forbinding to its receptor due to structural differences. Torsemidemediated modulation of GC, specifically mGC induces changes in cGMP andcGMP mediated pathways.

In an embodiment of the present invention, an extended release oraldosage formulation is considered wherein a tablet is manufactured by wetgranulation comprising torsemide or a pharmaceutically acceptable saltthereof as an active ingredient ranging from 27%-34% by weighthydroxypropyl methyl cellulose and 25-53% by weight high densitymicrocrystalline cellulose of nominal particle size of about 100micrometer; and 6.5-8% lactose monohydrate. In a preferred embodiment,when administered orally to a subject the T1/2 will increase between32-55% compared to that of a corresponding (by API weight) immediaterelease dosage form. In another embodiment, an aldosterone receptorantagonist or a pharmaceutically acceptable salt thereof is added,wherein torsemide and the aldosterone receptor antagonist are part ofthe extended release dosage formulation.

In another embodiment of the present invention, an extended release oraldosage formulation is considered wherein a tablet is manufactured by wetgranulation comprising torsemide or a pharmaceutically acceptable saltthereof as an active ingredient ranging from 27%-34% by weighthydroxypropyl methyl cellulose and 25-53% by weight high densitymicrocrystalline cellulose of nominal particle size of about 100micrometers; and 5-8% lactose monohydrate.

In an another embodiment, the extended release oral dosage formulationwill be administered orally to a subject, and Cmax decreases by 60-76%of a corresponding (by API weight) immediate release dosage form. In apreferred embodiment, the extended release oral dosage formulation whenadministered orally to a subject shall decrease AUC1-3 (1-3 hours afterdrug administration and measured as hr/ng·ml−1) between 48-67% andincreases AUC8-10 (8-10 hours after drug administration and measured ashr/ng·ml−1) between 149-263% compared to that of a corresponding (by APIweight) of the immediate release dosage form.

In another embodiment, a method of producing wet granules of an extendedrelease oral dosage formulation is contemplated wherein mixing torsemidewith either 27-34% by weight or 32-34% by weight hydroxypropyl methylcellulose with 25-53% by weight of high density microcrystallinecellulose, and 5-8% by weight of lactose monohydrate results in a finalweight of granules.

It is an object of the present invention to provide an extended releaseoral dosage formulation with torsemide and a matrix component. Further,the matrix component may be selected from HPC, HPMC, glyceryl behenate,or a polyethylene glycol glyceride and combinations thereof. Theformulation can be formed into a tablet for dosing. The concentration oftorsemide may vary from a range of about 0-20% by weight. In alternativeembodiments, the Torsemide may be present in ranges of 5-10% by weightor up to 50% by weight. A binder may be used in the extended oralrelease dosage form and be between 25-75% of the formulation by weight.In certain embodiments, the binder may be a microcrystalline cellulosebinder.

In alternative embodiments, lactose or lactose monohydrate may be usedin a range of 0-20% by weight. For treatment in patients with diabetes,an extended oral release formulation is contemplated and torsemide ispresent in conjunction with an ACE inhibitor, an aldosterone receptorantagonist, a calcium channel blocker, a thiazide diuretic, anangiotensin receptor blocker, an alpha blocker, and a beta blocker.

The ACE inhibitor aspect can be alacepril, benazepril, captopril,cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat,imidapril, lisinopril, perindopril, quinapril, ramipril saralasinacetate, temocapril, trandolapril, ceranapril, moexipril, quinaprilatand spirapril.

The method of making the formulation contains the steps of forming amixture of torsemide and a matrix component, granulating the mixtureinto particles and sizing them, and re-forming the mixture into anextended release tablet formulation. Preferred embodiments include about5 wt % to about 10 wt % of Torsemide or a pharmaceutically acceptablesalt thereof; about 10 wt % to about 40 wt % of a matrix component;about 50 wt % to about 60 wt % of at least one binder; about 5 wt % toabout 15 wt % of lactose; about 1 wt % to about 3 wt % of talc; andabout 0.5 wt % to about 1 wt % of magnesium stearate.

Alternative tablet formulations provide for about 6-7% by weight oftorsemide and 15-35% by weight of the matrix component. The matrixcomponent can be hydroxy propyl cellulose (HPC), hydroxpropyl methylcellulose (HPMC), glyceryl behenate, a polyethylene glycol glyceride andcombinations thereof.

In an embodiment, the present invention comprises a combination therapyof a Sodium-glucose linked transporter (SGLT) inhibitors and torsemidein an extended release formulation for prevention and treatment ofrecurrent heart failure (HF) in patients with type 2 diabetes (T2D) andchronic kidney disease (CKD).

SGLT inhibitors are currently marketed as adjunctive therapy for type 2diabetes mellitus (T2D). They include empaglifozin, canaglifozin,dapaglifozin and ertugliflozin. In clinical trials, SGLT inhibitors haveshown substantial reduction in cardiovascular (CV) events;hospitalization for HF, and mortality. Although the glycosuric effect ofSGLT inhibitors is diminished progressively in chronic kidney disease(CKD) and they have little effect on reducing HbA1c at eGFR>50 ml/min.However, they have shown to improve CV outcomes and reduced mortality inpatients with eGFR<50 ml/min despite reduced effect on HbA1c. Theimproved CV outcomes are accompanied by weight loss and fall in bloodpressure (BP). These effects were confirmed for empagliflozin anddapagliflozin. These data suggest that although CKD limits the efficacyof SGLT inhibitors in reducing HbA1c, since CKD limits the load ofglucose filtered by the kidney and hence the renal excretion of glucose,the diuretic and natriuretic effects are still preserved. However, thesestudies were limited to patients with eGFR>30 ml/min whose mean eGFR was54 ml/min (CKD3a). The effect of SGLT inhibitors on CVD and GFRprotection are expected to the same specifically in patients with CKD 3bor 4.

Mechanism of Diuretic and Natriuretic Efficacy of SGLT Inhibitors inCKD:

It was originally assumed that increased urine output and sodiumexcretion in patients with T2D treated with SGLT inhibitors representedan osmotic diuresis from the effects of the large increase in excretionof glucose. However, this cannot explain their maintained, or everimproved diuretic, natriuretic and antihypertensive effectiveness in CKDwhere glycosuria is minimal. This has been modeled recently based onrenal micropuncture data in a T2D rat with CKD induced by ⅚ nephretomy(nx). The model predicts that in a ⅚ Nx T2D rat, there would be higherluminal glucose delivery (due to hyperfiltration in remaining nephrons)that will enhance the effect of SGLT inhibitors to increase tubularfluid glucose concentration. Since the proximal tubule (PT) is highlypermeable, this will reduce PT fluid reabsorption and consequentlyreduce the tubular fluid [Na] to such an extent that net parcellular Na+transport in the permeable S3 segment of the proximal tubule downstreamfrom the site of action of SGLT inhibitors (S2 segment) is reversed,leading to substantial net tubular Na+ secretion into the tubular fluid.Thus, SGLT inhibitors provide unexpectedly good adjunctive diuretictherapy for HF in T2D in patients with CKD 3b/4, but they are notsufficient as solo therapy for HF. Moreover, combined SGLT1 and 2inhibitors therapy could enhance this effect by further reducing glucosereabsorption and tubular fluid [Na] in the proximal tubule that shouldfurther enhance tubular Na+ secretion.

Mechanism of Preservation of GFR by SGLT Inhibitors in DiabeticNephropathy:

Most patients with T2D have “hyperfiltration” due to reducedpre-glomerular (afferent arteriolar) tone that increases the glomerularcapillary pressure (P_(GC)) and glomerular plasma flow and therebyincreases the single nephron glomerular filtration rate (SNGFR). Reducedafferent arteriolar tone in T2D is attributed to inhibition of voltagegated calcium channels by hyperglycemia. The mechanism of renalprotection in patients with diabetic nephropathy by renin systeminhibitors entails a differential reduction in the post-glomerular(efferent arteriolar) tone that reduces the P_(GC). SGLT inhibitors havebeen shown to correct hyperfiltration by a unique mechanism distinctfrom ACEI's or ARB's. Thus, inhibition of Na+/Cl− and glucosereabsorption in the PT increase the delivery of Na+ and Cl− to the loopof Henle and the macula densa segment. The increased Na+/Cl− deliveryactivates the tubulo-glomerular feedback (TGF) response to causevasoconstriction of the afferent arteriole that corrects thehyperfiltration. This activation of TGF is maintained over 2 weeks ofobservation of SGLT inhibitor administration to diabetic rats.Activation of TGF should produce an initial fall in GFR and renal bloodflow (i.e. correction of hyperfiltration), followed by a stabilizationover time, as was indeed seen in patients with diabetic nephropathy. Forexample, empagliflozin caused an acute fall in GFR and renal blood flow(RBF) in patients with T1D. Thus, SGLT inhibition provides an excitingand novel approach to prevent loss of GFR in diabetic nephropathy thatshould be additive with the effects of ACEIs and ARBs but effects inpatients with more than modest CKD are not presently explored. This is agroup in greatest need since most physicians withdraw ACEIs and ARBs inpatients with CKD3b and beyond. Moreover, hyperkalemia in this group canpresent an urgent need to change therapy. SGLT inhibitor and loopdiuretics both have K⁺ losing, rather than K⁺ retaining, actions thatwould be beneficial in these patients and thereby would fill an unmetneed. Indeed, an additive hypokalemic effect of an SGLT inhibitor and aloop diuretic over one week are shown in healthy subjects. A combinationof SGLT inhibitor/loop diuretic provides a unique opportunity to combator prevent hyperkalemia and thereby to liberalize much neededACE/ARB/MCA therapy. In addition, any preservation of eGFR by SGLTinhibitor therapy should improve CV and HF outcomes since a reduction inGFR is a strong predictor of adverse outcomes in CHF. However, acuteinhibition of SGLT1/2 with phlorizin reduces RBF and GFR in diabetic rat(i.e. corrected hyperfiltration) similar to effects of a SGLT inhibitoralone.

Synergy Between SGLT Inhibitors with Loop Diuretic:

Repeated administration of an SGLT inhibitor to rats with T2D led to asustained reduction in the fraction of filtered Na⁺ and Cl⁻ reabsorbedin the proximal tubule and yet enhanced the fraction of Na⁺ and Cl⁻reabsorbed in the loop of Henle. If the loop of Henle is reabsorbingmore Na⁺ and Cl⁻ during SGLT inhibitor therapy, loop diuretics thatinhibit coupled Na⁺/K⁺/2Cl⁻ reabsorption in the loop of Henle shouldbecome more effective. This hypothesis was tested in a cross-over trialof healthy volunteers where dapagliflozin alone produced only a modestnatriuresis. A loop diuretic, bumetanide, produced a bigger natriuresis.However, when given after one week of dapaglifozin therapy, thenatriuresis with bumetanide was 36% greater. Moreover, when given afterone week of bumetanide therapy, the natriuresis with dapagliflozin was190% greater. These data demonstrate two-way adaptive natriureticsynergy between a SGLT inhibitor and a loop diuretic. Thus, a SGLTinhibitor and loop diuretic is an ideal combination for patients withCHF with T2D.

Torsemide ER an Improved Loop Diuretic:

Furosemide is the most widely prescribed loop diuretic but it suffersfrom several defects: highly variable bioavailability (10-80%), frequenthypokalemia and inability to reduce BP in essential hypertension. Incontrast, torsemide has high and predictable bioavailability of 80-100%that is unaffected by CHF or CKD, it does not cause hypokalemia at usualtherapeutics doses and is a good anti-hypertensive agent. This has ledto the suggestion that torsemide be the loop diuretic of choice for CHF.Indeed, in a head-to-head comparison of patients with HF randomized tofurosemide or torsemide on discharge from hospital with acute HF, thosereceiving torsemide had approximately half the number of readmission forHF over the follow up period. Despite high bioavailability and lowvariability of torsemide compared to furosemide, it too, like all otherloop diuretics, suffers from a very short (3-5 hour) duration of action,which leaves the nephron available to reabsorb Na+ and fluid during thetime after the diuretic has been eliminated and the thereby limits theirtherapeutic efficacy. Moreover, the torrential diuresis (“Niagaraeffect”) is distressing for elderly patients and can cause incontinencethat contributes to non-compliance. Accordingly, extended releasetorsemide was developed that has 8-12 hour duration of action in vivostudies. In a cross over trial in normal volunteers, torsemide ER led totwice the loss of Na+ and fluid in 24 h after a single dose, accompaniedby a fall in body weight, but no increase in K+ excretion. Whereas thesubjects receiving torsemide immediate release, similar to those inprior trials with furosemide, had a significant 22% reduction in GFR,when give torsemide ER, there was no significant fall in GFR. Almost allpatients with CHF and CKD 3 or 4 require a loop diuretic, and failure ofloop diuretic efficacy is a major cause for relapse and readmission fromCHF. Thus, a combination of a SGLT inhibitor with torsemide ER providesthe best available Na+ and fluid-depleting therapy and to providesuperior clinical outcomes in patients with T2D, CKD and/or CHF.

SGLT1 vs SGLT2 Inhibitors:

SGLT1 is co-expressed with GLUT1 in the GI Track (GIT), heart and S3segment of the proximal tubule. Sotagliflozin is an SGLT1/2 inhibitorthat can improve glycemic control and may address unmet needs. The SGLT1inhibition component impairs glucose absorption in the GIT and therebymoderates post-prandial hyperglycemia. Assuming the GIT effects arepreserved in CKD, this may provide additional HbA1c lowering effect dueto SGLT1 inhibition. Recent studies in patient with T1D and CKD3bindicates that SGLT1/2 inhibitors are better in reducing HbA1c in thesepatients as compared to SGLT2 specific inhibitors. Clearly, thesestudies need to be confirmed in a large group of patients but SGLT1/2inhibitors hold promise.

Anti-Cardiac Fibrotic Effects of a SGLT Inhibitor and Torsemide ERCombination:

The beneficial effects of SGLT inhibition on HF are apparent within afew weeks, and generally are not achieved with other anti-hyperglycemicdrugs. This has led to the suggestion that they may have direct cardiaceffects. One potential mechanism shown for dapagliflozin in a rat modelof myocardial infarction is an anti-oxidant/anti-fibrotic action. Themechanism is clear and entails reduced collagen-1 cardiac accumulation.Nonetheless, SGLT2 is not expressed in the human heart, and the benefitsof dapagliflozin may have been mediated in part via off-target effectson SGLT1. Similarly, animals or patients with CHF treated with torsemidealso have reduced cardiac fibrosis. This effect is specific fortorsemide and is not seen with furosemide. The mechanism seems to beindependent of mineralocorticosteroid receptor (MCR) inhibition oraldosterone receptor antagonist. Torsemide also prevents cardiacfibrosis in a rat model of CKD. Thus, both SGLT2 inhibitors andtorsemide can inhibit cardiac fibrosis in models or patients with CHFand CKD perhaps by independent and additive mechanisms.

Compared to present therapy with a SGLT inhibitor and furosemide forpatients with T2D, CHF and CKD, a novel combination of a SGLT inhibitorwith torsemide ER is expected to have the following benefits:

-   -   1. Enhanced Na+ and fluid loss providing enhanced protection        from recurrent CHF,    -   2. Enhanced reduction in HbA1c providing anti-hyperglycemic        efficacy at more advanced levels of CKD,    -   3. Enhanced Quality of Life (QoL) with less Niagara effect and        incontinence leading to better compliance,    -   4. Enhanced protection against hyperkalemia thereby opening a        window of opportunity to liberalize ACEI/ARB/MCR antagonist        therapy,    -   5. Enhanced anti-fibrotic effects in the heart and vasculature        that may be especially beneficial in patients with HF and        preserved ejection fraction, preventing development of HF in        patients with diabetes, CKD and/or HT, who currently lack a        targeted therapy.

TABLE 7 Dosage Formulations and Selectivity for SGLT2 and SGLT1 ChemicalBioavail- Tmax T½ Dose Selectivity Entity ability (h) (h) (mg)(SGLT2:SGLT1) Canagliflozin 65% 1-2 10 100-300 1:414  Dapagliflozin 78% 1-1.5 13  5-10 1:1200 Empagliflozin 95% 1.5 13 10-25 1:2500Ertugliflozin 87% 2-3 12.5  5-15 1:2000 Ipragliflozin 92 1  15 1:360 Tofogliflozin 98% 1.1 5.5 1:3000 Sotagliflozin 70% 1.9 2.5 1:20 

A fixed-dose combination of extended release torsemide (ER-T) andaldosterone receptor antagonist for the treatment ofuncontrolled/resistant hypertension.

Uncontrolled or resistant hypertension is common. It is defined as ablood pressure that is not at goal despite the prescription of adiuretic and two other antihypertensive drugs. It carries an increasedrisk of cardiovascular and cerebrovascular complications because of theadverse effects of sustained hypertension. It frequently complicateshypertension in patients with chronic kidney disease (CKD) or diabetesmellitus (DM) in whom hyperkalemia is a recognized complication oftherapy with drugs that block the renin-angiotensin-aldosterone system(RAAS). The recently published PATHWAY-2 trial reported thatspironolactone was very effective in reducing BP in this population andrelated this to a high proportion of such patients withhyperaldosteronism. Despite their effectiveness, mineralocorticoidantagonist (MRAs) suffer from adverse feminizing system (forspironolactone) and hyperkalemia (a class effect) that their use orbecomes an indication for their withdrawal. Moreover, even underclinical trial conditions, there is a high rate of non-adherence toantihypertensive treatment revealed by in patients withuncontrolled/drug resistant hypertension. The number of patients withuncontrolled (drug resistant hypertension, and the problems of theirmanagement, have grown considerably with the publication of the SPRINTtrial and its conclusion that the Systolic Blood Pressure (SBP) goalshould be 120 rather than 140 mmHg for hypertension with cardiovascularrisk. Thus, there is a considerable and growing unmet need for a saferand more effective and better tolerated MRA regimen to treat thesepatients.

A combined therapy with torsemide ER and Eplerenone addresses this unmetneed from several viewpoints.

-   -   Providing Eplerenone as an ER formulation should enhance its        effectiveness since its half-life of 4-6 hours is marginal for        once daily dosing. This would reduce the need for the poorly        tolerated spironolactone.    -   The once daily combination dosage should enhance drug        compliance. This is a major problem in this population.    -   The combination should provide additive anti-hypertensive        effectiveness yet subtractive (balanced) effects on serum        potassium. This should extend MRA therapy to the many patients        developing, as at risk for hyperkalemia.    -   The great effectiveness should bring more patients to goal at        the new lower BP levels. This should reduce cardiovascular and        cerebrovascular complications.    -   This may place patients with CKD and diabetes mellitus (DM) who        are at special need for MRA therapy, yet at special risk of        hyperkalemia, within a group that could receive MRA therapy

Torsemide, like furosemide and bumetanide, is a loop diuretic thatinhibits the coupled reabsorption of Na+/K+/2Cl− via the luminal Na—K—Clcotransporter-2 (NKCC2) in the thick ascending limb of the loop ofHenle. Since about 22% of filtered Na+ is reabsorbed by thecotransporter, torsemide is a highly potent natriuretic agent. Itsharply increases the excretion of Na+, Cl− and fluid along with a K+excretion at higher doses.

However, the abrupt natriuresis with loop diuretic is followed by aperiod of decrease Na+ excretion and repeat doses lead to diminishingresponse. This restricts the therapeutic effectiveness of all currentloop diuretics in ridding the body of excessive Na+ and fluid. Fivefactors have been identified that account for these unfavorable effects.First, is increased reabsorption of Na+ by a downstream nephron site inthe distal tubule and collecting duct. Second, is release of renin andangiotensin that stimulate aldosterone and thereby reabsorption of Na+in the collecting duct. Third, is the generation of a metabolicalkalosis from preferential excretion of Cl− with relative retention ofHCO3− that impairs the inhibition of NKCC2 by loop diuretics. Fourth, isa fall in glomerulus filtration rate (GFR) of about 20% seen with loopdiuretic administration. Fifth, is the very short duration of action of3-5 hours of all loop diuretics that leave the renal tubules free toreabsorb NaCl during the majority of the day, even when the diuretic isgiven twice daily.

Eplerenone, like spironolactone and its metabolites binds to, andinhibits, the mineralocorticoid receptor (MR) that is predominantlyexpressed in the collecting duct, where 1-2% of filtered Na+ is normallyreabsorbed. Activation of MR by aldosterone decreases the degradation ofthe beta subunit of the luminal sodium channel (ENaC) that enhancescellular Na+ entry and thereby the lumen-negative trans-epithelialelectrical potential that facilitates the secretion of K+ and H+ intotubular fluid. The result of MR blockade is a gradual and modestincrease in Na+ excretion accompanied by a decreased excretion of K+ andH+ with the propensity to cause hyperkalemia and metabolic acidosis. Theefficacy of a MR antagonist (MRA) is increased during condition ofhyperaldosteronism including edematous states and patients with drugresistant hypertension, as demonstrated in PATHWAY-2 trial. Althoughshown to have considerable benefits in patients with some categories ofheart failure or renal disease, the clinical effectiveness of MRAs hasbeen limited by adverse effects. These include feminizing effects thatare limited to spironolactone and hyperkalemia, especially in patientsreceiving ACEI/ARB therapy or with CKD or DM that is a class effect.This precludes the use of MRAs in many patients who might otherwisebenefit.

Additive and/or synergistic actions of extended release torsemide andEplerenone in patients with hypertension are:

First,

Eplerenone enhances the NaCl loss with torsemide ER by severalmechanisms:

-   -   Blocking the effect of angiotensin dependent aldosterone        secretion and thereby reducing post-diuretic Na+ retention by        blocking aldosterone-dependent upregulated reabsorption in the        collecting duct.    -   Correcting metabolic alkalosis        Second,

Torsemide ER enhances the NaCl loss with Eplerenone and reduce itsprincipal adverse effect of hyperkalemia by several mechanisms—

-   -   Increasing the delivery of Na+ to the site of MR action in the        collecting duct, thereby making Eplerenone more effective in        ridding the body of Na+ and fluid    -   Increasing the excretion of K+ at higher doses, thereby reducing        K+ retention and hyperkalemia

Both torsemide and Eplerenone are effective anti-hypertensive drugs.Although both likely reduce BP in part by reduction in body fluidvolume, they act on different segments of the nephron and thereforeshould have additive actions.

Torsemide is reported not to prevent aldosterone-mediated MR activationin cardiomyocytes and thereby should not impair the cellular action ofEplerenone. Both torsemide and spironolactone prevent cardiac remodelingin dilated cardiomyopathy.

Thus, a combination of extended release torsemide and Eplerenone exert sbeneficial additive effects in reducing body fluid and blood pressure,and beneficial effects in limiting the adverse effects of hyperkalemiaoften encountered with MRA therapy.

The principal benefits of the torsemide ER and Eplerenone combinationare in the management of patients with uncontrolled hypertension whohave developed hyperkalemia on spironolactone therapy. These patientshave received a diuretic plus two additional anti-hypertensive drugs(often an ACEI or ARB plus a CCB) but have not achieved a BP to meet theJNC8 target level recommendations by the ACC/ASH/AHA expert group.

In the drawings and specification, there have been disclosed typicalpreferred embodiments of the invention and, although specific terms areemployed, they are used in a generic and descriptive sense only and notfor purposes of limitation, the scope of the invention being set forthin the following claims.

A method for treating a patient clinically diagnosed for chroniccongestive heart failure, chronic kidney disease, hypertension anddiabetes individually or any combinations thereof, the method comprisingthe steps of determining serum and urinary creatinine levels to estimateglomerular filtration rate, diabetes by obtaining a blood glucose samplefrom the patient; and performing or having performed an assay on thesample to determine if the patient has diabetes; and measuring ejectionfraction or serum brain natriuretic peptide (BNP) levels to assess heartfailure; and if the patient has heart failure and diabetes with orwithout chronic kidney disease, then orally administering torsemide ERand SGLT inhibitor combination to the patient wherein torsemide amountis 5 mg to 200 mg per day and SGLT inhibitor amount is 1 mg-100 mg perday; and if the patient has uncontrolled with or without heart failure,then orally administering torsemide and aldosterone receptor antagonistcombination to the patient wherein torsemide amount is 5 mg to 200 mgper day and aldosterone receptor antagonist amount is 1 mg-200 mg perday

The invention has been described herein using specific embodiments forthe purposes of illustration only. It will be readily apparent to one ofordinary skill in the art, however, that the principles of the inventioncan be embodied in other ways. Therefore, the invention should not beregarded as being limited in scope to the specific embodiments disclosedherein, but instead as being fully commensurate in scope with thefollowing claims.

The invention claimed is:
 1. An extended-release oral dosage composition manufactured by wet granulation comprising torsemide or a pharmaceutically acceptable salt thereof, 5 wt % to 40 wt % of hydroxypropyl methyl cellulose; 25 wt % to 53 wt % of high-density microcrystalline cellulose of nominal particle size about 100 micrometer, 2 wt % to 8 wt % of lactose monohydrate, and an inhibitor of sodium-glucose linked transporter (SGLT) or a pharmaceutically acceptable salt thereof, wherein the inhibitor of SGLT is formulated using a hydrophilic matrix.
 2. The composition of claim 1, wherein the inhibitor of SGLT is specific to SGLT isoform 1 (SGLT1).
 3. The composition of claim 1, wherein the inhibitor of SGLT is specific to SGLT isoform 2 (SGLT2).
 4. The composition of claim 1, wherein the inhibitor of SGLT is specific to both SGLT isoform 1 and isoform 2 (SGLT1 and 2).
 5. A method of treating uncontrolled hypertension comprising administration to a patient in need thereof a therapeutically effective amount of the oral dosage formulation comprising between 5-200 mg of torsemide or a pharmaceutically acceptable salt thereof, 27 wt % to 34 wt % of hydroxypropyl methyl cellulose, 25 wt % to 53 wt % of high density microcrystalline cellulose of nominal particle size about 100 micrometer, 5 wt % to 8 wt % of lactose monohydrate, between 1-200 mg of an aldosterone receptor antagonist or a pharmaceutically acceptable salt thereof, wherein the torsemide and the aldosterone receptor antagonist are comprised in an extended release dosage formulation.
 6. The method of treatment of claim 5, wherein the patient has a serum potassium level of more than 4.0 mmol/l.
 7. The method of treatment of claim 5, wherein the patient has a glomerulus filtration rate (GFR) of less than 50 ml/min/1.73 m².
 8. The method of treatment of claim 5, wherein the patient has a glomerulus filtration rate (GFR) of less than 50 ml/min/1.73 m² and a serum potassium level of more than 4.0 mmol/l.
 9. The method of treatment of claim 5, wherein the patient is further diagnosed with congestive heart failure.
 10. A method of treating congestive heart failure (CHF) comprising clinical diagnosis of CHF in a patient and oral administration of the composition of claim
 1. 11. The method of treatment of claim 10, wherein the patient has a serum potassium level of more than 4.0 mmol/l.
 12. The method of treatment of claim 10, wherein the patient has a glomerulus filtration rate (GFR) of less than 50 ml/min/1.73 m².
 13. The method of treatment of claim 10, wherein the patient has a glomerulus filtration rate (GFR) of less than 50 ml/min/1.73 m² and a serum potassium level of more than 4.0 mmol/l.
 14. The method of treatment of claim 10, wherein the patient is further diagnosed with diabetes.
 15. The method of treatment of claim 14, wherein the patient has a serum potassium level of more than 4.0 mmol/l.
 16. The method of treatment of claim 14, wherein the patient has a glomerulus filtration rate (GFR) of less than 50 ml/min/1.73 m².
 17. The method of treatment of claim 14, wherein the patient has a glomerulus filtration rate (GFR) of less than 50 ml/min/1.73 m² and a serum potassium level of more than 4.0 mmol/dl.
 18. A method of treating diabetes which comprises administering to a patient in need thereof the oral dosage composition of claim
 1. 19. The method of treatment of claim 18, wherein the patient has a serum potassium level of more than 4.0 mmol/l.
 20. The method of treatment of claim 18, wherein the patient has a glomerulus filtration rate (GFR) of less than 50 ml/min/1.73 m². 